中国神经再生研究(英文版) ›› 2021, Vol. 16 ›› Issue (3): 561-566.doi: 10.4103/1673-5374.293157

• 原著:神经损伤修复保护与再生 • 上一篇    下一篇

Liproxstatin-1是谷胱甘肽过氧化物酶4抑制引起的少突胶质细胞铁死亡的有效抑制剂

  

  • 出版日期:2021-03-15 发布日期:2020-12-17
  • 基金资助:

    中国国家自然科学基金项目(8167217182197074819300708162010801881772342);国家重点研究开发计划项目(2019YFA0112100);天津市自然科学基金项目(19JCZDJC34900

Liproxstatin-1 is an effective inhibitor of oligodendrocyte ferroptosis induced by inhibition of glutathione peroxidase 4

Bao-You Fan1, #, Yi-Lin Pang1, #, Wen-Xiang Li1, #, Chen-Xi Zhao1, Yan Zhang1, Xu Wang1, Guang-Zhi Ning1, Xiao-Hong Kong2, Chang Liu2, Xue Yao1, *, Shi-Qing Feng1, *   

  1. 1 International Cooperation Base of Spinal Cord Injury, Tianjin Key Laboratory of Spine and Spinal Cord, Department of Orthopedics, Tianjin Medical University General Hospital, Tianjin, China; 2 School of Medicine, Nankai University, Tianjin, China
  • Online:2021-03-15 Published:2020-12-17
  • Contact: Xue Yao, Ph.D, xueyao@tmu.edu.cn; Shi-Qing Feng, PhD, MD, sqfeng@tmu.edu.cn.
  • Supported by:
    This study was supported by the National Natural Science Foundation of China, Nos. 81672171 (to XY), 81972074 (to XY), 81930070 (to SQF), 81620108018 (to SQF), and 81772342 (to GZN); the National Key R&D Program of China, No. 2019YFA0112100 (to SQF); the Natural Science Foundation of Tianjin of China, No. 19JCZDJC34900 (to XY).

摘要:

作者前期研究显示,铁死亡在脊髓损伤急性期及亚急性期中具有重要作用。由于少突胶质细胞中谷胱甘肽含量低而铁含量高,因而容易在中枢神经系统损伤后发生铁死亡。但是少突胶质细胞的铁死亡机制仍不清楚。(1)实验通过谷胱甘肽过氧化物酶4抑制剂RSL-3建立了少突胶质细胞系OLN-93铁死亡模型。发现随着RSL-3诱导浓度的增加,细胞模型中活性氧和丙二醛的浓度也显著增加。RSL-3可抑制细胞中主要的抗铁死亡通路胱氨酸/谷氨酸反向转运体/谷胱甘肽/谷胱甘肽过氧化物酶4,且长链脂肪酸-CoA连接酶4表达减少;(2)实验还评价了几种铁死亡抑制分子的作用效果,发现Liproxstatin-1比依达拉奉和去铁胺的抑制细胞铁死亡的效果更显著。因而进一步分析Liproxstatin-1的作用机制,发现其不仅能抑制线粒体脂质过氧化,还能恢复谷胱甘肽、谷胱甘肽过氧化物酶4和铁死亡抑制蛋白1的表达;(3)说明抑制谷胱甘肽过氧化物酶4的表达可以诱导少突胶质细胞发生铁死亡,且Liproxstatin-1是一种强效的铁死亡抑制剂,可能成为在中枢神经疾病的潜在药物。

关键词: 中枢神经, 脊髓, 损伤, 修复, 少突胶质细胞, 细胞死亡, 因子, 通路, 氧化

Abstract: Our previous studies showed that ferroptosis plays an important role in the acute and subacute stages of spinal cord injury. High intracellular iron levels and low glutathione levels make oligodendrocytes vulnerable to cell death after central nervous system trauma. In this study, we established an oligodendrocyte (OLN-93 cell line) model of ferroptosis induced by RSL-3, an inhibitor of glutathione peroxidase 4 (GPX4). RSL-3 significantly increased intracellular concentrations of reactive oxygen species and malondialdehyde. RSL-3 also inhibited the main anti-ferroptosis pathway, i.e., SLC7A11/glutathione/glutathione peroxidase 4 (xCT/GSH/GPX4), and downregulated acyl-coenzyme A synthetase long chain family member 4. Furthermore, we evaluated the ability of several compounds to rescue oligodendrocytes from ferroptosis. Liproxstatin-1 was more potent than edaravone or deferoxamine. Liproxstatin-1 not only inhibited mitochondrial lipid peroxidation, but also restored the expression of GSH, GPX4 and ferroptosis suppressor protein 1. These findings suggest that GPX4 inhibition induces ferroptosis in oligodendrocytes, and that liproxstatin-1 is a potent inhibitor of ferroptosis. Therefore, liproxstatin-1 may be a promising drug for the treatment of central nervous system diseases.

Key words: cell death, central nervous system, factor, ferroptosis, oligodendrocyte, oxidation, pathway, repair, spinal cord injury